Biomedical subjects
Publications and source records attributed to A Tichelli.
4 of the 198 patients treated by bone marrow transplantation in Basel, Switzerland, with a follow-up of more than one year after therapy, developed a severe restrictive pneumopathy. In none of the 4 patients could an infectious pathogen be isolated, but all of them had signs of a chronic graft-versus-host disease. The 4 cases are described in detail.
Changes in hemostatic factors after bone marrow transplantation (BMT), with or without thrombotic complications, have already been described. The endothelium seems to be actively involved in such processes. Over a period of 2 years we evaluated various hemostatic factors, associated or not with endothelial stimulation, in 44 patients with BMT (40 leukemias and 4 aplastic anemias). Factor VIII activity (VIII:C), von Willebrand factor antigen (vWF:Ag), tissue plasminogen activator antigen (tPA), plasminogen activator inhibitor activity (PAI-1), antithrombin III, protein C and protein S were assayed before and 1, 3, 6, 12, 18, and 24 months after BMT. Factor VIII:C, vWF and tPA were found to be significantly increased 1-6 months after BMT, returning to normal later. Patients with acute graft versus host disease, fever or cyclosporin treatment had significantly higher VIII:C, vWF and tPA. The increase in these factors implies lasting stimulation of their release and/or synthesis from endothelial cells that is enhanced by some complications of BMT. The degree and character of these changes could favor activation of thrombotic processes.
The goal of this prospective randomized single-center study was the comparison of safety and efficacy of high-dose oral/intravenous fluconazole (400 mg daily) (group A) with oral nystatin plus miconazole inhalations (group B) in the prevention of fungal infections on a hemato-oncological isolation Ward. Of 157 patients admitted to the isolation ward during the study period only 90 (57%) were eligible for randomization; 22 (14%) had a fungal infection at admission. Of the 90 randomized patients, 89 were evaluable, 43 in group A and 46 in group B. The age, sex, diagnosis, planned therapy and risk factors for fungal infections at admission as well as the duration of neutropenia were in the same proportions in both groups. Oral thrush and mucocutaneous candidiasis were prevented in all patients of both groups, and 29 patients (32%: 17 in group A, 12 in group B) were discharged after successful prophylaxis (NS). Empiric amphotericin B was given according to predetermined criteria to 45 patients (51%: 23 group A, 22 group B; NS). Fluconazole significantly delayed the time before the start of intravenous amphotericin B. It was begun after a median of 10 days (0-45 days, range) of neutropenia below 0.5 x 10(9) granulocytes/l in group A and 7.5 days (0-26, range) in group B (P < 0.05). The duration of successful prophylaxis was significantly longer in group A (26 days median) than in group B (21 days, median) (P < 0.05). Systematic fungal infection was documented in 3 patients (1 group A, 2 group B; NS).
In a prospective open-labelled phase I/II trial we tested efficacy and tolerability of recombinant human interleukin-3 (rhIL-3) alone in patients with refractory severe aplastic anaemia (SAA). 15 patients with idiopathic (12 patients) or secondary (one post-hepatitic, one drug induced, one dyskeratosis congenita) SAA, refractory or relapsing after one to three courses of antilymphocyte globulin were included. 14 patients were transfusion dependent (RBC 14, platelet 12). RhIL-3 was planned for three patients each at five escalating dose levels of 1, 2, 4, 8 and 16 micrograms/kg, given daily as 24 h continuous infusion for 21 d. RhIL-3 was prematurely withdrawn at days 10 and 11 for adverse events in two patients. 9/15 patients showed an increase in WBC; 2/6 at the 1-2 micrograms/kg and 7/9 at the 4-16 micrograms/kg level, but no sustained effects were seen. No patient showed a response in platelet counts. Additionally, platelet and RBC transfusion requirements were unchanged pre and post study. All patients experienced one or more adverse event, mainly fever (15 patients), bleeding (nine patients), and headache (six patients). Occurrence of adverse events was dose related and the maximum tolerated dose was reached with 8 micrograms/kg. Five patients suffered serious adverse events. RhIL-3 as single growth factor and used alone is of minimal benefit in severe aplastic anaemia.
Bone marrow from 65 patients with aplastic anaemia (AA) was tested for stroma growth in short term cultures (2 weeks) and for colony formation by haemopoietic precursor cells during the course of their disease. In 18 untreated patients, mean stroma growth was 30% of normal and colony formation was virtually absent. After treatment with immunosuppression (IS), as estimated from 90 examinations in 54 patients, stroma growth was approximately 50% and colony growth approximately 10% of normal. Growth impairment of stroma and haemopoietic precursors persisted for 10 and more years after IS. Results of 2-week stroma cultures were compared with results of long term bone marrow cultures in 10 AA patients and 4 controls. At 2 weeks, growth of aplastic marrow was delayed compared to normal, but this difference became less evident with prolonged incubation time. In vitro growth abnormalities were compared with the clinical evolution after IS. The development of late haematological complications (paroxysmal nocturnal haemoglobinuria (PNH)) and myelodysplastic syndrome (MDS), did not correlate with the degree of stroma growth impairment. However, relapse of aplasia was associated with poor stroma growth: 8/29 patients with stroma confluence of < or = 30% during haematological remission versus 1/25 with stroma confluence of > 30% relapsed. We conclude that (i) the haematopoietic microenvironment is frequently coinvolved in the disease process of AA, (ii) a defect is detected in short term rather than in long term stroma cultures and, (iii) relapse is more frequent in patients with poor stroma growth.
Mobilized peripheral blood precursor cells (PBPC) are used with increasing frequency to restore autologous hematopoiesis following high-dose radio-chemotherapy. The success of this method has aroused interest in the use of mobilized PBPC for allogeneic transplants. This approach would eliminate the need for marrow aspiration and general anesthesia. In this project we tested the feasibility of allogeneic histoincompatible PBPC transplants in rabbits. Adult outbred Red Burgundy rabbits were used as donors, histoincompatible New Zealand White rabbits of the opposite sex as recipients. One individual donor was used for one individual recipient. Conditioning consisted of 10 Gy total body irradiation (TBI). Donor animals were pre-treated with recombinant human granulocyte colony-stimulating factor (rh G-CSF) given s.c. at 10 micrograms/kg daily. Three schedules of PBPC collection and reinfusion were tested in 3 groups of animals, each consisting of 5 donor recipient pairs: (A) PBPC were collected either on days -2, -1 and 0, and infused at once after TBI on day 0; (B) collected and infused on days 0, +2, +4, +7, +9, and +11; (C) collected on 3 consecutive days, cryopreserved for 1 month and infused on day 0 followed by 3 fresh donations on days +4, +8 and +11. The median amount of blood processed from donor animals was 470 ml (312-602) containing about 10 x 10(8) (5-71 x 10(8)) nucleated cells. Recipient animals received a median of 2.7 x 10(8) cells/kg equivalent to 9.6 x 10(4) colony-forming units granulocyte-macrophages (CFU-GM)/kg (data derived from Group C of the animals).(ABSTRACT TRUNCATED AT 250 WORDS)
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We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome.
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We report the case of a 70-year-old patient with B-cell chronic lymphocytic leukemia. During therapy with the new purine analog 2-chloro-deoxyadenosine (2-CDA) the patient developed Pneumocystis carinii pneumonia (PCP). Although the mechanism of action of 2-CDA suggests the incidence of opportunistic infections and therefore pneumocystis pneumonia, this is the first case of PCP among 140 patients of the Swiss study of 2-CDA. The mechanism of action of 2-CDA is described and the occurrence of PCP among patients without acquired immunodeficiency syndrome is discussed.
After organ transplantation, life-long immunosuppression is mandatory to prevent rejection. This is not the case after allogeneic bone marrow transplantation (BMT). The mechanisms of tolerance are little understood and there is little data about the required duration of immunosuppression. In a retrospective study we analyzed the use of cyclosporine A (CyA) treatment in all BMT patients who where transplanted in Basel from 1979 to 1991. 243 patients with a median age of 26 (2-49) years received CyA to prevent graft-versus-host-disease (GvHD) and rejection. 206 patients had leukemia, 26 severe aplastic anemia and 10 a lymphoproliferative disorder. All were treated according to a common CyA regimen with initial parenteral administration followed by oral treatment for a year; after 1988 treatment duration was reduced to 6 months. Drug dosage was adjusted according to clinical symptoms, plasma levels and toxicity. At relapse of the original disease CyA was always withdrawn. Three months after BMT 96% were still on CyA. After 6 months 79%, after 1 year 61%, after 2 years 29%, after 3 years 18%, after 4 years 15%, after 5 years 8% and after 8 years 2% of patients were still taking CyA. All 20 patients who are still alive 10 years after BMT are off CyA. CyA was administered parenterally for a median of 31 (5-147) days. Oral treatment started at day 25 (4-28). The oral dose was reduced 5 (1-20) times, increased once (1-75) and finally discontinued after a median time lapse of 1 year (14d-8y).(ABSTRACT TRUNCATED AT 250 WORDS)
UNLABELLED: Since October 1988 there has been an isolation ward at Basle Cantonal Hospital. Its purpose is to treat patients with high dose chemotherapy and bone marrow transplantation under protective isolation and by standardized criteria. The isolation ward has two sub-units, viz. the reverse isolation for neutropenic patients (8 single room units) and the LAF unit (5 laminar airflow units) for allogeneic bone marrow transplantation (BMT). Up to July 1992, 287 patients (152 males and 133 females) required 527 hospitalizations. The median age was 41 (5-82) years in the reverse isolation unit and 28 (4-61) years in the LAF unit. Bed occupation was 90% and 82% throughout the period. 71% of patients were from the Basle area and the rest from elsewhere in Switzerland or from other countries. DIAGNOSIS: acute leukemias (112); myelodysplastic or myeloproliferative syndromes (52); severe aplastic anemia or agranulocytosis (46); lymphoproliferative syndromes (50); solid tumors (28). Indications for hospitalisation: BMT (107); complications after BMT (infections, GvHD) (63); chemotherapy on protocols of SAKK (105); other chemotherapies (64); antilymphocyte globulin or growth factor treatment (27); splenectomies (18); neutropenic fever (62); patient work-up (59); terminal care (20). Patients in reverse isolation were hospitalized for a median 17 (1-142) days; in the LAF unit for 52 (1-121) days.(ABSTRACT TRUNCATED AT 250 WORDS)
Maintenance chemotherapy for up to 3 years is traditionally given to patients with acute lymphoblastic leukaemia (ALL) achieving complete remission. We questioned the value of such maintenance therapy in adult patients treated with intensive induction/consolidation. In a phase II study (SAKK 33/86) 63 patients between 17 and 72 years of age (median 27 years) with newly diagnosed ALL were treated with three intensive cycles of marrow-ablative chemotherapy. All subtypes were included. No maintenance phase was added. 53 patients (84%) entered a complete remission (CR) and 21 (33%) continue to be in unmaintained remission for 11-69 months (median 21 months). The disease-free survival of patients achieving CR and completing all three cycles is 40% at 3 years, with a 95% confidence interval of +/- 19%. These findings are comparable to the results of conventional studies. We conclude that maintenance therapy might not be needed in all adult ALL patients. Its value should be tested in a randomized trial. For patients failing, novel approaches are needed to improve outcome in adult ALL.
One hundred and seventy patients with severe aplastic anemia (SAA) were treated in Basel, from 1976 to 1992. Forty one underwent bone marrow transplantation (BMT) and 129 antilymphocyte globulin (ALG) therapy. As of January 1, 1993, 99 of the 170 patients are alive (58% +/- 7%) and the probability to be alive at 15 years is 54% +/- 4%. Until now, 29 patients have developed a clonal complication. All occurred within the ALG group. Nine patients developed a myelodysplastic syndrome (MDS), 16 patients paroxysmal nocturnal hemoglobinuria (PNH) and 4 patients both, PNH and MDS. The cumulative risk of developing a clonal complication after ALG-therapy is 42% +/- 13% at 15 years; for MDS this risk is 26% +/- 8% and for PNH 25% +/- 5%. The development of a clonal disease directly affects long term prognosis. The survival of the patients with stable disease is 81% +/- 10% and 36% +/- 13% for those with clonal evolution (p = 0.001). The most important risk factor is the type of treatment. In contrast to patients treated with ALG, none of the patients treated with BMT developed MDS or PNH (p < 0.001). No other clinical parameter, such as age, sex, etiology of SAA, severity of the disease and splenectomy correlate with an increased risk of developing this complication. In contrast, morphological parameters at the time of diagnosis, during bone marrow regeneration and at remission are indications in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)
We compared two non-radioactive PCR methods, a single step PCR and a nested PCR, for detecting bcr-abl transcripts in patients with chronic myelogenous leukemia (CML). The nested PCR assay was about thousand times more sensitive than the single step PCR. In 75 clinical samples tested in parallel, the sensitivity for the single step PCR and the nested PCR was 43.2% and 91.9%, respectively. In all 17 samples of 9 patients before bone marrow transplantation (BMT), bcr-abl transcripts were detected by the single step PCR. After BMT, 5 (9.8%) of 51 samples of 4 patients were positive by the single step PCR and 17 (33.3%) of 7 patients by the nested PCR. These data indicate that single step PCR may miss minimal residual disease whereas nested PCR is a sensitive alternative to the use of radioactive probes.
33 aplastic episodes in 24 patients undergoing bone marrow ablative therapy for the treatment of haematological malignancies were monitored with automated flowcytometric counts with particular emphasis to BLAST, MONO (monocytes) and LUC (large unstained cells) determined by Technicon H1, and MFR and HFR reticulocytes determined by Sysmex R1000. We found regular pattern of appearance of flowcytometric parameters, which were predictive for leucocyte recovery. A transient increase of BLAST to > 10% and MONO+LUC to > 0.08 x 10(9)/l were predictive for leukocyte recovery after aplastic episodes following ABMT, BMT and high dose AraC therapy, but not after conventional chemotherapy. The prognostic value of MFR+HFR reticulocytes increase over 5% was limited to ABMT and BMT. This report demonstrates the capabilities of automated flowcytometric analysis in early prediction of haematological recovery.